Download Micronised Purified Flavonoid Fraction

ADIS DRUG EVALUATION
Drugs 2003; 63 (1): 71-100
0012-6667/03/0001-0071/$33.00/0
© Adis International Limited. All rights reserved.
Micronised Purified Flavonoid Fraction
A Review of its Use in Chronic Venous Insufficiency,
Venous Ulcers and Haemorrhoids
Katherine A. Lyseng-Williamson and Caroline M. Perry
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:
C. Allegra, Servizio di Angiologia, Ospedale San Giovanni, Rome, Italy; J. Bergan, Vein Institute of La Jolla,
La Jolla, California, USA; E. Bouskela, Laboratório de Pesquisas em Microcirculação, Universidade do
Estado do Rio De Janeiro, Rio De Janeiro, Brazil; D.L. Clement, Department of Cardiology, University
Hospital, Ghent, Belgium; P.D. Coleridge Smith, Department of Surgery, University College London
Medical School, The Middlesex Hospital, London, England; P. Godeberge, Unité de Proctologie
Médico-Chirurgicale, Institut Mutaliste Montsouris, Paris, France; Y.-H. Ho, School of Medicine, James Cook
University, Townsville, Queensland, Australia; A. Jawien, Department of Surgery, Ludwik Rydygier
University Medical School, Bydgoszcz, Poland; M.C. Misra, General Surgery Department, Mafraq Hospital,
Abu Dhabi, United Arab Emirates; A.-A. Ramelet, Place Benjamin-Constant, Lausanne, Switzerland;
G.W. Schmid-Schönbein, Institute of Biomedical Engineering, University of California, San Diego,
California, USA; F. Zuccarelli, Département Angiologie et Phlébologie, Hôpital Saint Michel, Paris, France.
Data Selection
Sources: Medical literature published in any language since 1980 on micronised purified flavonoid fraction, identified using Medline and
EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the
reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the
company developing the drug.
Search strategy: Medline search terms were ‘diosmin hesperidin’ or ‘micronised purified flavonoid fraction’. EMBASE search terms were
‘diosmin hesperidin’ or ‘micronised purified flavonoid fraction’. AdisBase search terms were ‘diosmin hesperidin’ or ‘micronised purified
flavonoid fraction’. Searches were last updated 2 December 2002.
Selection: Studies in patients with chronic venous insufficiency, venous ulcers or haemorrhoids who received micronised purified
flavonoid fraction. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials
with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Micronised purified flavonoid fraction, diosmin hesperidin, chronic venous insufficiency, venous ulcers, haemorrhoids,
pharmacodynamics, pharmacokinetics, therapeutic use.
Contents
Summary
. . . . . . . . . . . . . . . . . . . . . . .
1. Introduction . . . . . . . . . . . . . . . . . . . . . .
2. Pharmacodynamic Properties . . . . . . . . . . .
2.1 Effect on Venous Tone . . . . . . . . . . . . .
2.2 Effect on Microcirculation . . . . . . . . . . .
2.2.1 Leukocyte Activation and Adhesion . .
2.2.2 Capillary Permeability and Resistance
2.2.3 Haemorheological Changes . . . . . .
2.3 Effect on Lymphatics . . . . . . . . . . . . . .
3. Pharmacokinetic Properties . . . . . . . . . . . .
3.1 Absorption and Distribution . . . . . . . . . .
3.2 Metabolism and Elimination . . . . . . . . . .
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4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 In Patients with Chronic Venous Insufficiency (CVI) . . . . . . . . . . . .
4.1.1 Comparative Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2 Long-Term Treatment . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 In Patients with Venous Ulcers . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Effects on Venous Ulcer Healing . . . . . . . . . . . . . . . . . . . .
4.2.2 Cost-Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 In Patients with Haemorrhoids . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.1 Comparison with Placebo . . . . . . . . . . . . . . . . . . . . . . . .
4.3.2 MPFF plus Fibre in Comparative Trials . . . . . . . . . . . . . . . . .
4.3.3 In Pregnant Patients . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.4 To Reduce Bleeding After Haemorrhoidectomy . . . . . . . . . . .
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Place of Micronised Purified Flavonoid Fraction in the Management of CVI,
Venous Ulcers and Haemorrhoids . . . . . . . . . . . . . . . . . . . . . . . . .
7.1 CVI
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2 Venous Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3 Haemorrhoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Summary
Abstract
Micronised purified flavonoid fraction (MPFF) [Daflon® 500mg1], an oral
phlebotropic drug consisting of 90% micronised diosmin and 10% flavonoids
expressed as hesperidin, improves venous tone and lymphatic drainage, and reduces capillary hyperpermeability by protecting the microcirculation from inflammatory processes. The absorption of diosmin is improved by its
micronisation to particles with a diameter <2µm.
Compared with placebo, MPFF 500mg twice daily significantly decreased
ankle or calf circumference, and improved many symptoms of chronic venous
insufficiency (CVI) and plethysmographic parameters in two randomised, double-blind, 2-month studies. Improvement in symptoms was parallelled by an improvement in health-related quality of life in a nonblind, 6-month trial.
Significantly more venous leg ulcers ≤10cm in diameter completely healed
with MPFF 500mg twice daily plus standard management (compression and local
treatment) for 2–6 months than with standard management alone or with placebo
in a nonblind and a double-blind trial. The addition of MPFF to standard management was cost effective in a retrospective pharmacoeconomic analysis of the
6-month trial.
Compared with placebo, the duration and/or intensity of individual symptoms
of grade 1 or 2 acute internal haemorrhoids improved significantly with 3 tablets
of MPFF 500mg twice daily for 4 days then 2 tablets of MPFF 500mg twice daily
for 3 days. Two tablets of MPFF 500mg daily for 60 or 83 days reduced the
frequency, duration and/or severity of acute haemorrhoidal symptoms and improved the overall signs and symptoms of chronic (recurrent) haemorrhoids com-
1 Also registered as Ardium®, Alvenor®, Arvenum® 500, Capiven®, Detralex®, Elatec®, Flebotropin®, Variton®, Venitol®;
use of tradenames is for product identification purposes only and does not imply endorsement.
 Adis International Limited. All rights reserved.
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
73
pared with placebo. Compared with a control group, MPFF significantly reduced
the risk of secondary bleeding after elective haemorrhoidectomy.
In clinical trials, MPFF had a tolerability profile similar to that of placebo; the
most frequently reported adverse events were gastrointestinal and autonomic in
nature.
In conclusion, MPFF is a well established and well tolerated treatment option
in patients with CVI, venous ulcers, or acute or chronic internal haemorrhoids.
MPFF is indicated as a first-line treatment of oedema and the symptoms of CVI
in patients in any stage of the disease. In more advanced disease stages, MPFF
may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment when surgery is not indicated or is unfeasible.
The healing of venous ulcers ≤10 cm in diameter is accelerated by the addition
of MPFF to standard venous ulcer management. MPFF may reduce the frequency,
duration and/or intensity of symptoms of grade 1 or 2 acute internal haemorrhoids,
and also the severity of the signs and symptoms of chronic haemorrhoids.
Pharmacodynamic
Properties
MPFF, an oral phlebotropic and vascular protective agent consisting of 90%
micronised diosmin and 10% flavonoids expressed as hesperidin, increases venous tone, improves lymphatic drainage and reduces capillary hyperpermeability.
By reducing the expression of some endothelial adhesion molecules, MPFF inhibits the activation, migration and adhesion of leukocytes, which leads to a
reduction in the release of inflammatory mediators and thereby a reduction in
capillary hyperpermeability.
Two tablets of MPFF 500mg daily reduced venous distensibility and capacitance, and improved venous tone in patients with various types of venous insufficiency.
Several indices of inflammation in the microcirculation are reduced by MPFF.
Plasma levels of some markers of endothelial activation (intercellular adhesion
molecule-1 and vascular cell adhesion molecule) and surface expression of some
leukocyte adhesion molecules (monocyte or neutrophil CD62L) were significantly reduced from baseline with 2 tablets of MPFF 500mg daily for 60 days in
patients with CVI. Capillary hyperpermeability decreased with 2 or 3 tablets of
MPFF 500mg daily resulting in a decrease in oedema in patients in two trials.
Daily administration of 1–4 tablets of MPFF 500mg for 1–3 months had beneficial effects on venous oximetry measurements (e.g. increases from baseline in
oxygen pressure, oxygen saturation or pH, and decreases from baseline in carbon
dioxide pressure) in patients with mild to moderate CVI in two studies. In patients
with CVI, 2 tablets of MPFF 500mg daily for 4 weeks increased red blood cell
velocity in capillaries; however, relative capillary packed cell volume also increased.
In patients with severe CVI, 2 tablets of MPFF 500mg daily for 28 days
decreased intralymphatic pressure and the diameter of lymphatic capillaries and
increased the number of functional lymphatic capillaries compared with baseline
values.
Pharmacokinetic
Properties
Most information on the pharmacokinetics of oral MPFF relates to the diosmin
portion of the drug. Diosmin is rapidly transformed in the intestine by intestinal
flora and absorbed as its aglycone, diosmetin; the unchanged form of diosmin
does not appear to be absorbed. Approximately half of an oral 500mg dose of
radiolabelled MPFF was absorbed within 48 hours of administration in healthy
volunteers. Micronisation of diosmin increased oral absorption compared with
 Adis International Limited. All rights reserved.
Drugs 2003; 63 (1)
74
Lyseng-Williamson & Perry
nonmicronised diosmin (57.9 vs 32.7% of a radiolabelled dose was absorbed
0–168 hours postdose). Diosmetin has a rapid distribution period followed by a
slower elimination period. Animal studies have demonstrated that radiolabelled
diosmetin and/or its metabolites are widely distributed throughout the body.
Diosmetin is rapidly and extensively degraded to phenolic acids or their glycine conjugate derivatives, which are eliminated in the urine; unmetabolised
diosmin and diosmetin are not excreted in the urine. The predominant metabolite,
3-hydroxy-phenylpropionic acid, is mainly eliminated in its conjugated form.
Unidentified metabolites may be responsible for the pharmacological activity of
diosmin.
Approximately half of a radiolabelled dose of diosmin was eliminated in the
faeces as unchanged diosmin and diosmetin. Elimination of micronised diosmin
is relatively rapid (≈34% of the dose excreted in the urine and faeces over the
first 24 hours and ≈86% over the first 48 hours). There are no known drug interactions with MPFF.
Therapeutic Efficacy
In Patients with Chronic Venous Insufficiency: Compared with placebo,
MPFF 500mg twice daily for 2 months significantly decreased ankle and calf
circumferences from baseline in two double-blind trials in 36 and 150 patients;
improvements were also seen in the symptoms of CVI (e.g. functional discomfort,
nocturnal cramps and sensations of leg heaviness, swelling or heat) and plethysmographic parameters (e.g. venous capacitance, distensibility and emptying
time).
The efficacy of 2 tablets of MPFF 500mg daily was maintained in the longterm nonblind treatment (6–12 months) of patients with symptoms of CVI.
Patients with or without venous reflux in the large (n = 4527) 6-month Reflux
Assessment and Quality of Life Improvement with Micronised Flavonoids study
showed a significant improvement in CEAP (Clinical signs, Etiology, Anatomical distribution, and Pathophysiological dysfunction) classification. Moreover,
both groups of patients also showed a significant improvement in their healthrelated quality of life, as measured by the Chronic Venous Insufficiency Questionnaire global index scores.
In double-blind, 2-month trials in patients with CVI, 2 tablets of MPFF 500mg
daily was more effective than the same nominal dosage of nonmicronised diosmin
in improving most of the subjective symptoms and objective parameters of CVI;
MPFF 500mg improved the signs and symptoms of CVI regardless of the daily
administration schedule (2 tablets in either the morning or the evening, or 1 tablet
twice daily).
Effects on Venous Ulcer Healing: MPFF 500mg twice daily plus standard
management (compression and local therapy) for 2–6 months was more effective
than standard management alone or with placebo in the complete healing of
venous leg ulcers ≤10cm in diameter in a nonblind and a double-blind trial.
Venous leg ulcers with a diameter ≤10cm were completely healed in 32 or 46.5%
of patients receiving 2 tablets of MPFF 500mg daily for 2 or 6 months compared
with 13% of patients receiving placebo for 2 months or 27.5% of patients in the
control group in the 6-month trial. Ulcers >10cm in diameter did not completely
heal in either the active-treatment or placebo group during the 2-month trial.
Compared with the control group in the longer trial, MPFF reduced mean ulcer
area (80 vs 65%) and discomfort related to ulcer (64.8 vs 38.3% of patients); this
trial did not include ulcers >10cm in diameter.
 Adis International Limited. All rights reserved.
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
75
In a retrospective pharmacoeconomic analysis of the 6-month trial, 2 tablets
of MPFF 500mg daily was cost-effective in the treatment of venous ulcers compared with the control group receiving standard venous ulcer treatment. Based
on the cost per healed ulcer over 6 months, the cost-effectiveness ratio in the
MPFF group was 1026 euros (EUR) compared with EUR1872 in the control
group (year of costing 1998).
In Patients with Haemorrhoids: In two randomised, double-blind, placebocontrolled trials, MPFF 500mg (3 tablets twice daily for 4 days then 2 tablets
twice daily for 3 days) significantly reduced the duration and/or intensity of symptoms of acute internal haemorrhoids (e.g. bleeding, pain, and anal discharge)
compared with placebo. After the first few days of treatment, systemic and topical
anaesthetics were used less by patients receiving MPFF than patients receiving
placebo.
In two double-blind trials, treatment with MPFF 500mg twice daily for 60 or
83 days reduced the frequency, duration and/or severity of acute haemorrhoidal
symptoms in patients with chronic symptoms of haemorrhoids compared with
placebo. Relapses of bleeding were prevented in 18 or 36% more patients receiving MPFF than those receiving placebo; MPFF also effectively treated the symptoms and signs of chronic haemorrhoids.
In a randomised, nonblind trial, MPFF 500mg (3 tablets twice daily for 5 days,
then 2 tablets twice daily for 3 weeks) plus fibre (ispaghula husk) resolved bleeding from nonprolapsed internal haemorrhoids as effectively as with rubber band
ligation plus fibre and more rapidly than with fibre alone.
In a noncomparative trial in pregnant women, MPFF 500mg (6 tablets daily
for 4 days, then 4 tablets for 3 days) reduced median symptom scores for bleeding,
pain, rectal discomfort and rectal exudation from baseline. Maintenance treatment with MPFF 500mg twice daily in the antenatal and 30-day postnatal periods
reduced the duration of relapses of symptoms of acute haemorrhoids compared
with the patient’s history.
The proportion of patients with secondary postoperative bleeding after open
pedicular haemorrhoidectomy was less in patients receiving MPFF 500mg (2
tablets three times daily for 3 days then 1 tablet three times daily for 4 days) than
in the control group (0.9 vs 6.1%).
Tolerability
In clinical trials, MPFF was well tolerated with most reported events being mild
and transitory. The adverse events most commonly associated with MPFF are
gastrointestinal (e.g. abdominal pain, gastric discomfort, nausea, dyspepsia, vomiting and diarrhoea) or autonomic (e.g. insomnia, drowsiness, vertigo, headache
and tiredness) in nature. Combined data from clinical trials in patients with CVI
or haemorrhoids indicated that the incidence of adverse events was similar in
2850 patients receiving 2 tablets of MPFF 500mg daily and 225 patients receiving
placebo (10 vs 13.9% of patients). Gastrointestinal and autonomic events were
reported by 6.9 and 1.7% of patients receiving MPFF. Adverse events were the
reason for discontinuation in the trials of 1.1% of MPFF recipients compared with
3.2% of placebo recipients.
The incidence or nature of adverse events was not changed by long-term treatment (1 year) with 2 tablets of MPFF 500mg daily, dosages of MPFF 500mg of
up to 6 tablets daily for 7 days, age ≥70 years or the presence of concomitant
diseases (i.e. hypertension, atherosclerosis, diabetes mellitus, neurological/psy-
 Adis International Limited. All rights reserved.
Drugs 2003; 63 (1)
76
Lyseng-Williamson & Perry
chiatric disease or alcoholism). Two tablets of MPFF 500mg daily for 1 year did
not modify blood pressure or laboratory parameters.
Dosage and
Administration
MPFF is available as 500mg tablets and is administered orally. Prescribing information for MPFF may differ between the more than 100 countries (including
9 countries in the EU and 20 other European countries) that have approved its
use. In general, MPFF is indicated for the treatment of organic or idiopathic CVI
of the lower limbs with symptoms of heavy legs, pain or nocturnal cramps, acute
haemorrhoidal attacks or chronic haemorrhoids. In CVI, the recommended dosage is 2 tablets daily (as a single dose in the morning or evening or 1 tablet twice
daily); in acute haemorrhoidal attacks, 2 tablets three times daily for 4 days
followed by 2 tablets twice daily for 3 days; and in chronic haemorrhoids, 2 tablets
daily. MPFF does not interact with any drugs. Caution is recommended when
administering MPFF to patients who are breast feeding.
1. Introduction
Chronic venous insufficiency (CVI), the deficient return of venous blood flow in the lower
limbs, is a widespread disorder that involves either
the superficial venous system or both the deep and
superficial systems.[1-4] Characteristics of CVI include signs (e.g. telangiectases, varicose veins, oedema, skin changes or venous ulcers) or subjective
symptoms (e.g. aching, nocturnal cramps or the
sensation of heat, burning, tingling, heaviness or
tiredness in the legs) related to venous stasis resulting from venous hypertension.[1,2]
Venous hypertension develops from venous reflux and/or vein obstruction and is most commonly
caused by abnormalities in the venous wall or
valves, or by changes resulting from a previous
venous thrombosis.[1] The causes and symptoms of
CVI involve not only structural and functional abnormalities of the veins but also of the skin microcirculation.[1,2] Varicose veins, which may develop
from the abnormal distensibility of connective tissue in the vein wall, are the most common manifestation of CVI;[1] however, some patients may
have functional CVI associated with a venular
pathology, but no clinical evidence of varicose
veins.[5] Infiltration of inflammatory cells (macrophages) into the venous wall and leaflets is associated with leukocyte activation[6,7] and expression
of membrane adhesion proteins.[8] Skin changes
(e.g. venous eczema, skin pigmentation) and ultimately venous ulcers may occur as a result of im Adis International Limited. All rights reserved.
pairment in the microcirculation.[1] Venous ulcers
usually involve a loss of skin with a well defined
margin and have a base covered with a yellow exudate; the surrounding skin is erythematous,
hyperpigmented or liposclerotic.[2] They are often
painful and may take a long time to heal. Indeed,
most ulcers (50–75%) take 4–6 months to heal and
20% continue to be open at 2 years.[2]
Numerous risk factors for varicose veins have
been suggested, including lifestyle factors (e.g.
occupations that involve prolonged standing[9] or
sitting[10]) or a family history of varicose veins.[2,4]
The development of varicose veins in patients already susceptible to the condition may be accentuated by obesity or pregnancy.[2,4,9] The risk of venous ulcer is directly related to the degree and
pattern of venous insufficiency,[11,12] and may also
be associated with a history of venous thrombosis.[13]
The severity of CVI may be assessed by the
Clinical signs, Etiology, Anatomical distribution,
and Pathophysiological dysfunction (CEAP) classification system.[14] The clinical signs of CEAP
are divided into the following classes.
• C0: no visible or palpable signs of venous disease.
• C1: telangiectases, reticular veins and malleolar
flare.
• C2: varicose veins.
• C3: oedema without skin changes.
• C4: skin changes ascribed to venous disease
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
(e.g. pigmentation, veno us eczema and
lipodermatosclerosis).
• C5: as C4 with healed ulceration.
• C6: as C4 with active ulceration.[14]
Because of its high prevalence, cost of investigation and treatment, and associated loss of working days, CVI is associated with a substantial socioeconomic cost.[1,2,4,12] Medical care costs of
CVI accounted for 1–3% of the total annual health
care budgets in European countries,[4,15,16] and the
annual direct plus indirect costs of CVI are approximately one billion US dollars for each of Germany, France and the UK.[1,2] CVI was ranked as
the 14th most frequent cause of temporary absence
from work and the 32nd most frequent cause of
retirement due to disability in Brazil.[17] Venous
ulcers incur the highest cost per patient of all the
clinical presentations of CVI because of its chronic
nature and high prevalence in the population.[4]
Estimates of the prevalence of varicose veins
and venous ulcers vary considerably and depend
on the definition of the condition and methodology
of assessment.[4,9,12] According to populationbased epidemiological studies in various countries,[9] 25–32% of woman and 7–40% of men have
varicose veins. In the Framingham study, the incidence per year of varicose veins was 2.6% in
women and 1.9% in men.[18] The prevalence of
open or open plus healed venous ulceration is
≈0.3[9] and ≈1%.[9,19] Women have a prevalence of
venous ulcers that is approximately two to three
times greater than in men.[9] The prevalence of
both varicose veins and venous ulceration increases consistently with age.[2,4,9,12]
Haemorrhoids result from the distal displacement of the anal cushions and are a very common
and widespread condition.[20,21] They are classified as either external or internal depending on
their origin (i.e. below or above the dentate line)
and both types may thrombose.[22] External haemorrhoids are painful; internal haemorrhoids may
cause rectal bleeding and/or discomfort. Symptoms are chronic with recurrent self-resolving
acute episodes.[23] The treatment of haemorrhoids
depends on the origin and grade of the lesion.[22]
 Adis International Limited. All rights reserved.
77
Internal haemorrhoids are graded into the following categories by the extent of prolapse (the extent
to which the haemorrhoid descends into the anal
canal and out of the anus).[22]
• Grade 1: haemorrhoidal tissue is present and
identifiable and the main symptom is bleeding.
• Grade 2: haemorrhoids prolapse with a bowel
movement but return spontaneously.
• Grade 3: haemorrhoids prolapse and require
manual replacement.
• Grade 4: haemorrhoids remain prolapsed despite all efforts at reduction and are often associated with some degree of mucosal prolapse.
Various causes of haemorrhoidal disease have
been proposed (e.g. increased maximum resting
anal pressure, intrinsic weakness in the blood vessel wall, excessive arterial flow, secondary obstruction of outflow and increased intra-abdominal
pressure) but its pathophysiology is not completely
understood.[21,22,24,25] Haemorrhoids have been associated with many factors including diet, fibre intake, constipation and diarrhoea; however, studies
are conflicting in their conclusions on the effect of
these factors on the development of haemorrhoidal
disease.[21,24]
Reports of the prevalence and incidence of
haemorrhoids are often anecdotal and are influenced by the definition of haemorrhoids, data collection methods and population of the study.[21,24]
In a nation-wide questionnaire in the US,[26] the
prevalence of haemorrhoids was 4.4%; the prevalence was greatest between the ages of 45 and 65
years and there was an equal distribution of
haemorrhoidal disease between men and women.
Micronised purified flavonoid fraction (MPFF)
[Daflon® 500mg] is a well established oral
flavonoid with phlebotropic and venoprotective
properties.[3,27] It consists of 90% micronised diosmin and 10% flavonoids expressed as hesperidin
(which differs from diosmin by the absence of a
double bond between two carbon atoms) [figure 1].
Diosmin is synthesised from hesperidin, which is
extracted from a type of immature small orange.
The micronisation of diosmin to particles with a
diameter <2µm has improved the oral absorption
Drugs 2003; 63 (1)
78
Lyseng-Williamson & Perry
O
HO
CH2
O
O
O
OH
CH3
OCH3
HO
HO
OH
O
OH
O
OH
OH
Diosmin
O
HO
CH2
O
O
O
OH
CH3
OCH3
HO
HO
OH
O
OH
OH
O
OH
Hesperidin
Fig. 1. Chemical structure of diosmin and hesperidin.
of MPFF.[28] This article reviews the pharmacological properties and therapeutic efficacy of orally
administered MPFF in the management of patients
with CVI, venous ulcers or internal haemorrhoids.
Although venous ulcers result from CVI (CEAP
clinical class C5 and C6), this more severe disease
stage is discussed separately from CVI because
disease management and clinical trial design in patients with venous ulcers differ from those in patients with CVI.
2. Pharmacodynamic Properties
The major pathological event in CVI of the
lower limbs is a maintained elevation of venous
pressure, which is a consequence of venous reflux,
obstruction and/or risk factors of venous disease
(e.g. prolonged standing or heat).[1,12,29,30] This
chronic venous hypertension leads to disturbances
of the microcirculation, the site of fluid exchange
with interstitial tissues. The activation, migration
and adhesion of leukocytes results in a local inflammatory response and is associated with an increase in capillary permeability and fragility,[30,31]
and parenchymal cell apoptosis.[32] The lymphatic
system can compensate for the increase in fluid
outflow into the surrounding tissues in the early
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stages of the disease; if CVI persists or worsens,
oedema develops because the lymphatic system
becomes overloaded and can no longer handle the
excess fluids.[30] Free radicals and other cytotoxic
substances released by the inflammatory response
may in turn lead to trophic changes that may ultimately culminate in the development of venous ulcers;[29] however, the precise sequence of events
that leads to venous ulceration is not yet clear.[33]
The pathogenesis of haemorrhoids may involve
the stagnation and stasis of blood in the vascular
plexuses of the anal cushions.[34] Venous stasis
may lead to inflammation resulting in the increased
permeability, fragility and necrosis of the vessel
wall in the anal cushion and result in bleeding.
MPFF, a phlebotropic and vascular protective
agent, increases venous tone, improves lymphatic
drainage and protects the microcirculation from inflammatory processes and apoptosis.[3,27,28,35] By
reducing the expression of some endothelial adhesion molecules,[36-39] MPFF inhibits the activation,
migration and adhesion of leukocytes at the capillary level.[32,39-43] This leads to a reduction in the
release of inflammatory mediators such as oxygenfree radicals, prostaglandins and thromboxane,[44-46]
resulting in a decrease in capillary hyperpermeability.[35,41,47-49] An overview of the pharmacodynamic properties of MPFF in vitro and in
animals is presented in table I. Data on the pharmacodynamic properties of oral MPFF in various
patient groups (e.g. patients with CVI, oedema or
abnormal capillary fragility) are reviewed in sections 2.1–2.3. The pharmacodynamic properties of
MPFF in patients with haemorrhoids have not been
examined.
2.1 Effect on Venous Tone
By increasing venous tone and thereby reducing
venous capacitance, distensibility and stasis,
MPFF reduced the venous hyperpressure present
in patients with CVI.[58,59] Compared with placebo,
MPFF significantly improved venous haemodynamics in three double-blind, placebo-controlled,
crossover trials in patients with various types of
venous insufficiency (reported together in one paDrugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
79
Table I. Overview of the pharmacodynamic properties of micronised purified flavonoid fraction (MPFF) in vitro and in animals
Venous tone
Prolongs the vasoconstrictor effect of noradrenaline (norepinephrine) on the vessel wall and reduces blood venous stasis in vitro[50]
Increases mechanical tension on bovine metacarpal vein rings in vitro[51]
Increases Ca2+ sensitivity of the contractile apparatus in rat isolated femoral vein in vitro[52]
Inhibits increases in red blood cell, haematocrit and plasma protein concentrations elicited by the upright position in dogs[53]
Microcirculation
Inhibits intercellular adhesion molecule-1 expression in ischaemia/reperfusion skeletal muscle injury in rats[39]
Inhibits leukocyte adhesion and/or migration after ischaemia/reperfusion injury in hamster skin fold[40-42] or rat skeletal muscle,[39] oxidant
challenge in hamster cheek pouch[43] and venular mesenteric occlusion/reperfusion in rats[32]
Inhibits oxygenated free radical production in zymosan-stimulated human neutrophils[45] or mouse macrophages[46] in vitro
Inhibits synthesis of prostaglandin E2 or F2α and thromboxane B2 in inflammatory granuloma in rats[44]
Inhibits the increase in microvascular permeability induced by bradykinin or ischaemia in rat cremaster muscle[47] and histamine,
bradykinin, leukotriene B4 ischaemia/reperfusion[41] or oxidant challenge in hamster cheek pouch[48]
Improves microvascular reactivity and functional capillary density after ischaemia/reperfusion in hamster cheek pouch[54]
Reduced parenchymal cell apoptosis in the mesentery microcirculation and microhaemorrhages into the tissue after venular mesenteric
occlusion/reperfusion in rats[32]
Inhibits platelet functions in rats[55]
Lymphatic drainage
Increases contractility of sheep mesenteric lymphatic collecting ducts in vitro[56]
Increases the frequency of spontaneous contractions in bovine mesenteric lymphatics in vitro[51]
Improves lymphatic drainage in sheep[56] and dogs[57]
Decreases thigh weight, protein concentration in tissue and fibroblast number in rats with acute leg lymphostasis[30]
per).[58] The efficacy of MPFF was assessed using
mercury strain-gauge venous occlusion plethysmography. The optimal dose effect on venous
haemodynamic parameters was obtained with a
single-dose of 2 tablets of MPFF 500mg compared
with a single dose of 1 or 4 tablets of MPFF 500mg
in 18 women with venous insufficiency related to
a post-thrombotic syndrome. In ten women without venous pathology, a single dose of 2 tablets of
MPFF 500mg significantly improved venous distensibility beginning 1 hour after administration
and persisting for a further 4 hours (p < 0.05). After
treatment with 2 tablets of MPFF 500mg once
daily for 1 week, the significant effect on venous
distensibility was maintained for 24 hours (p <
0.05). A single dose of 2 tablets of MPFF 500mg
reduced venous capacitance both in healthy
women (n = 10) and in women with venous insufficiency related to postphlebitic syndrome (n = 10)
or pregnancy (n = 10).[58] Compared with placebo,
venous capacitance was significantly reduced
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from the first hour after administration (p < 0.05
for each patient group) and persisted for 2 hours (p
< 0.001).
Venous tone in female volunteers with abnormal venous elasticity and a high risk of developing
varicose veins improved with 2 tablets of MPFF
500mg daily for one month in a nonblind, controlled study.[59] Volunteers had symptoms of varicose
veins and abnormal venous tone but no obvious
varicose veins in one leg and symptomatic varicose veins in the opposite leg. Air plethysmography was used to evaluate changes from baseline
values in the elastic modulus of veins in the leg
without obvious varicose veins. A significant improvement from baseline in the elastic modulus
was shown in the 12 volunteers receiving MPFF
(increase of 4.0 × 103 N/m2; p < 0.02). In comparison, the elastic modulus did not change significantly from baseline in the 13 volunteers in the
control group who received no treatment.
Drugs 2003; 63 (1)
80
Lyseng-Williamson & Perry
2.2 Effect on Microcirculation
2.2.1 Leukocyte Activation and Adhesion
MPFF 500mg twice daily for 60 days reduced
several indices of inflammation in the microcirculation in 20 patients with CVI in a nonblind study
(figure 2).[36-38] Plasma levels of some adhesion
molecules are elevated in patients with CVI,[31,60]
and changes in their levels may be feasible markers
for response to therapy.[36,38] Plasma levels of intercellular adhesion molecule-1 (ICAM-1; binds
neutrophils/lymphocytes to endothelial cells) and
vascular cell adhesion molecule (VCAM; binds
lymphocytes/monocytes to vascular endothelium)
decreased significantly from baseline levels (p <
0.001; figure 2).[36] Moreover, there were significant reductions from baseline (p ≤ 0.003; figure 2)
in the surface expression of some leukocyte adhesion molecules (monocyte or neutrophil CD62L);
the decrease in monocyte or neutrophil CD11B
expression was not significant.[38] These reductions were seen both in patients with CVI with associated dermatological changes (CEAP clinical
35
**
Change from baseline (%)
30
**
*
*
25
20
15
10
5
B
M
C
D
D
N
C
C
M
11
11
62
D
D
C
B
L
L
62
AM
N
VC
IC
AM
-1
0
Fig. 2. Effect of oral micronised purified flavonoid fraction
(MPFF) on indices of inflammation in the microcirculation.
Changes from baseline values in plasma levels of intercellular
adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM) and cell surface fluorescence of monocyte (M)
or neutrophil (N) CD62L or CD11B in 20 patients with chronic
venous disease receiving MPFF 500mg twice daily for 60 days
in a nonblind study.[36,38] * p ≤ 0.003, ** p < 0.001 vs baseline.
 Adis International Limited. All rights reserved.
class C4; n = 10) and in patients with less severe
disease (C2 or C3; n = 10). Significant reductions
from baseline in the plasma levels of lactoferrin
(36%; p < 0.05)[36] or vascular endothelial growth
factor (42%; p < 0.02)[37] were shown only in the
C4 patient group.
2.2.2 Capillary Permeability and Resistance
MPFF decreased capillary hyperpermeability
resulting in a decrease in oedema in two trials.[35,49]
Increased capillary hyperpermeability is associated with ankle and foot oedema in patients with
CVI and leads to skin alteration and eventually ulcerations.[49] Capillary hyperpermeability, evaluated using the Landis isotope test with injection of
Tc99m-albumin, improved significantly (p < 0.05)
with 2 tablets of MPFF 500mg daily compared
with placebo in a randomised, double-blind, placebo-controlled, 6-week trial in 30 patients with
idiopathic cyclic oedema.[35] Weight loss (≥1.5 kg)
and a decreased sensation of swelling accompanied this reduction in labelled albumin retention (p
< 0.05 vs placebo for each parameter). In a nonblind, 4-week study using strain gauge plethysmography in patients with venous hypertension,
MPFF 500mg twice daily (n = 21) or 500mg three
times daily (n = 22) significantly decreased the
capillary filtration rate from baseline values in a
dose-dependent manner (p < 0.05).[49]
Compared with placebo, 2 tablets of MPFF
500mg daily improved capillary resistance in patients with abnormal capillary fragility in a
randomised, double-blind, 6-week trial.[61] At
week 6, capillary resistance assessed by the negative suction cup method increased from baseline to
a significantly greater extent with MPFF (from 149
to 261mm Hg; n = 48) than with placebo (from 151
to 163mm Hg at week 6; n = 48) [p < 0.001]. Patients receiving MPFF showed a significant improvement in the symptoms of capillary fragility
(spontaneous ecchymosis, epistaxis, purpura, petechiae, gingivorrhagia, metrorrhagia and conjunctival haemorrhage) [p < 0.001 vs placebo].
2.2.3 Haemorheological Changes
MPFF had beneficial effects on venous oximetry measurements in patients with mild to modDrugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
81
erate CVI in two studies.[62,63] During CVI, microcirculatory changes result in regional tissue hypoxia because of maldistribution of blood flow and
ischaemic areas.[63] Microcirculatory parameters
(assessed by transcutaneous oximetry) significantly improved from baseline (p < 0.001) with 1,
2 or 4 tablets of MPFF daily for 3 months in 90
evaluable patients with mild CVI in a randomised,
double-blind study (figure 3); compression therapy was discontinued before the trial.[62] Improvements in these parameters were not significantly
different across the three treatment groups.
In a nonblind study in 33 patients with mild or
moderate CVI in one leg,[63] 2 tablets of MPFF
500mg daily for 30 days significantly increased the
partial pressure of oxygen, oxygen saturation and
pH and decreased partial carbon dioxide pressure
(p < 0.01) compared with baseline values (assessed
by dorsal pedal venous oximetry measurements).
Oximetric data improved to a significantly greater
extent in the clinically uninvolved leg than in the
involved leg of patients (p < 0.05), which may have
been a result of lower capillary perfusion pressure
in the uninvolved limb.
Two tablets of MPFF 500mg daily improved
venous microangiopathy and resolved capillary
stasis by increasing red blood cell velocity in capillaries in a nonblind, 4-week study in 24 patients
with CVI.[64] Decreased red blood cell velocity and
increased packed volume are associated with stasis
in the microcirculation in the more advanced
stages of CVI. Red blood cell velocity increased
significantly from baseline to day 28 of treatment
(p < 0.05) and remained stable for a further 2 weeks
without treatment. However, relative capillary
packed cell volume increased significantly from
baseline to day 28 (p = 0.001) and then decreased
significantly after treatment was discontinued
from day 28 to day 42 (p = 0.001). The apparent
discrepancy between increased velocity and increased packed cell volume may be accounted for
by dissociation between viscosity and velocity at
the microcirculatory level (sigma effect) or an improvement in the flexibility of the red blood cells.
Other fluorescence capillaroscopic parameters did
not change between days 1 and 28 (i.e. maximum
intensity and appearance, disappearance or interstitial dwelling time).
Baseline
Day 90
80
70
*
*
*
60
mm Hg
50
40
*
*
*
30
20
10
0
500mg
1000mg
tcpO2
2000mg
500mg
1000mg
2000mg
tcpCO2
Fig. 3. Effect of oral micronised purified flavonoid fraction (MPFF) on transcutaneous oximetry parameters. Transcutaneous oxygen
(tcpO2) and carbon dioxide pressure (tcpCO2) at baseline and day 90 of treatment with 1, 2 or 4 tablets of MPFF 500mg daily; results
of a randomised, double-blind, 3-month study in 90 evaluable patients with mild chronic venous insufficiency.[62] * p < 0.001 vs
baseline.
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Drugs 2003; 63 (1)
82
Lyseng-Williamson & Perry
2.3 Effect on Lymphatics
Two tablets of MPFF 500mg daily improved the
lymphatic microangiopathy associated with CVI in
24 patients with severe CVI and no active ulceration in a noncomparative study reviewed by
Ramelet.[30] In patients with advanced stages of
CVI, increases in intralymphatic pressure and the
diameter and permeability of lymphatic capillaries
leads to the transendothelial diffusion of fluids.[65]
The diameter of lymphatic capillaries and the intralymphatic pressure both decreased significantly
(p < 0.001) from baseline after 28 days of treatment; the number of functional lymphatic capillaries increased significantly from baseline (p <
0.001).[30] These improvements may be attributable to an increase in lymphatic flow and drainage,
which leads to a reduction in oedema.
3. Pharmacokinetic Properties
Available pharmacokinetic data for oral MPFF
in humans are very limited (one double-blind
study[28]) and there are none in special patient
groups such as pregnant women or diabetic or elderly patients. Most information on the pharmacokinetics of MPFF relates to the diosmin portion of
the drug. Although the absorption characteristics
of MPFF are different from those of nonmicronised
diosmin, the metabolism of diosmin is similar
regardless of the formulation. Therefore, this section also includes some data from a study of the
pharmacokinetics of oral nonmicronised diosmin
in five healthy volunteers.[66] The pharmacokinetic
parameters of diosmin in several animal species
(including rats, dogs, rabbits and monkeys) have
been reported in data from the manufacturer.[67]
There are no known drug interactions with
MPFF.[68]
3.1 Absorption and Distribution
After oral administration, diosmin is rapidly
transformed in the intestine by intestinal flora and
absorbed as its aglycone, diosmetin.[66,67] Plasma
samples from humans or animals administered
diosmin did not show any traces of diosmin despite
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the sensitive assay methods used (i.e. high performance liquid chromatography and gas chromatography linked to mass spectrometry). An in vitro
study showed that 13C- and 14C-diosmin incubated
with human gut flora were transformed to
diosmetin, luteolin and phenolic acids.[67]
Approximately half of an oral 500mg dose of
radiolabelled MPFF was absorbed within 48 hours
of administration (table II) in a pharmacokinetic
study in 12 healthy male volunteers.[28] This double-blind, crossover study with a 14-day washout
period compared the absorption of radiolabelled
MPFF with that of nonmicronised diosmin.[28]
Because unabsorbed diosmin is not excreted in the
urine, absorption was evaluated based on the urinary elimination of radioactivity. Reduction in the
particle size of diosmin led to a significant increase in absorption; mean gastrointestinal absorption of micronised 14C-diosmin was significantly
greater than with nonmicronised 14C-diosmin
(57.9 vs 32.7% during 0–168 hours postdose; p =
0.0004).[28]
Diosmetin had a rapid distribution period followed by a slower elimination period in a singledose study of nonmicronised diosmin 10 mg/kg in
five volunteers.[66] The time to the peak plasma
concentration of diosmetin was 1 hour and plasma
concentrations started to decrease slowly after 2
hours; diosmetin was still detectable after 48
hours. The mean volume of distribution of
diosmetin was 62.1L, indicating that there was an
Table II. Excretion of micronised purified flavonoid fraction (MPFF)
into the urine and faeces. Percentage of the total radioactivity of a
single oral 500mg dose of 14C-MPFF excreted in the urine and
faeces in 12 healthy male volunteers.[28] Values are expressed as
mean values ± standard deviation
Time period (hours)
Percentage of total radioactivity
urinea
faecesb
0–24
31.1 ± 11.1
2.92 ± 6.56
0–48
49.5 ± 13.7
36.6 ± 28.5
0–72
54.4 ± 18.2
43.8 ± 30.3
0–168
57.9 ± 20.2
50.9 ± 24.2
a
Indicates the percentage of the dose that was absorbed from
the gastrointestinal tract. Excreted solely as metabolites.
b
Indicates the percentage of the dose that was excreted as unchanged (unabsorbed) diosmin and diosmetin.
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
extensive uptake of the compound by the tissues.[66] Animal studies have demonstrated that
radiolabelled diosmetin and/or its metabolites are
widely distributed throughout the body.[67]
3.2 Metabolism and Elimination
Diosmetin is rapidly and extensively degraded
to phenolic acids or their glycine conjugate derivatives, which are eliminated in the urine.[66,67] The
predominant metabolite in man is 3-hydroxyphenylpropionic acid which is mainly eliminated
in its conjugated form.[66,67] Metabolites found in
smaller amounts include other phenolic acids corresponding to 3-hydroxy-4-methoxybenzoic acid
and 3-methoxy-4-hydroxyphenylacetic acid and
3,4-dihydroxybenzoic acid.[66] It is possible that
unidentified metabolites may be responsible for
the pharmacological activity of diosmin.[67]
Elimination of micronised diosmin is relatively
rapid with ≈34% of the radiolabelled dose of 14Cdiosmin excreted in the urine and faeces over the
first 24 hours and ≈86% over the first 48 hours
(table II).[28] Unmetabolised diosmin and diosmetin are not excreted in the urine.[67] The cumulative excretion of the dose in the urine and faeces
was 100% (109 ± 23% 0–168 hours).[28] Approximately half of the dose was eliminated in the faeces
as unchanged diosmin and diosmetin. Unchanged
diosmin in the faeces corresponds to unabsorbed
diosmin as indicated by the very low biliary excretion of radioactivity in studies of 14C-diosmin in
rats.[67]
4. Therapeutic Efficacy
The efficacy of oral MPFF in the treatment of
patients with CVI (section 4.1), venous ulcers (section 4.2) or acute or chronic (recurrent) internal
haemorrhoids (section 4.3) has been evaluated in
comparative and noncomparative clinical trials.
Unless stated otherwise, patients in each treatment
group within each comparative trial were well
matched in terms of disease severity and other
baseline characteristics, and all data are for intention-to-treat groups.
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83
4.1 In Patients with Chronic Venous
Insufficiency (CVI)
Randomised, double-blind, 2-month studies
have evaluated the effectiveness of MPFF 500mg
twice daily in the treatment of functional or objective CVI compared with placebo[69,70] or diosmin
900 mg/day.[71] Additional details of the results of
the placebo-controlled trial by Chassignolle et
al.[69] have been reported by Tsouderos in a review
of three clinical trials of MPFF.[72] The effect of
various administration regimens of 2 tablets of
MPFF 500mg each day has also been examined.[73]
The long-term efficacy of 2 tablets of MPFF
500mg daily has been studied in two nonblind,
multicentre trials of 6- (Reflux Assessment and
Quality of Life Improvement with Micronised
Flavonoids [RELIEF] study)[74] or 12-months’ duration.[75]
The criteria for patient selection or exclusion
varied somewhat in each study. In general, adult
patients were eligible for enrolment in the trials if
they had clinical symptoms of CVI in the lower
legs attributable to primary varicose veins, postthrombotic syndrome or functional venous insufficiency.[70,71,73,75]
Patients were excluded from the trials if they
had concomitant active disease,[74,75] had other
vascular diseases,[70,71,73,75] had a history of venous surgery,[70,71,73,74] recent deep or superficial
venous thrombosis[71,73] or recent childbirth.[70]
Patients wearing surgical stockings or compression bandages were instructed to continue
wearing them;[70,71,73,74] in some studies patients
must have been using them for more than 2[71] or
3 months[70,73] prior to inclusion in the trial. There
was a higher proportion of women than men enrolled in the studies.[69-71,73-75]
The efficacy of MPFF was evaluated by the
change in clinical symptoms in the legs, ankle and
calf circumferences and/or plethysmographic parameters. The number and type of subjective clinical symptoms (e.g. functional discomfort, sensation of leg heaviness, leg pain, nocturnal cramps,
sensation of swelling, paraesthesia, redness and/or
cyanosis, sensation of heat and/or burning and
Drugs 2003; 63 (1)
84
Lyseng-Williamson & Perry
weakness) evaluated in the studies were somewhat
different in each study. Patient response was determined by changes in symptom score on a 4-[69-71,73,74]
or 5-point scale [75] where increasing numbers indicated increasing symptom severity. Functional
discomfort[73] or pain[74] were measured on 10point visual analogue scale in some of the trials. A
variety of noninvasive techniques, which correlate with changes in venous pressure, have been developed for objectively quantifying the severity of
CVI. These include strain gauge plethysmography
(e.g. venous distensibility at various venous occlusion pressures and duration of venous outflow after
removal of venous occlusion)[69,72] and duplexultrasonography (e.g. venous reflux time).[74]
In the RELIEF study, changes in CEAP clinical
classification were used to assess differences in the
severity and in the evolution of symptoms and
signs of CVI during MPFF treatment in patients
with or without venous reflux.[74] In addition, the
study used the Chronic Venous Insufficiency
Questionnaire (CIVIQ), the first health-related
quality-of-life scale specific for CVI, to evaluate
the effects of MPFF on health-related quality of
life.[74] CIVIQ is a 20-question self-administered
questionnaire with a range of scores from 0–100
where 100 indicates a very good health-related
quality of life.[76]
4.1.1 Comparative Trials
Comparisons with Placebo
Compared with placebo in two randomised,
double-blind, placebo-controlled trials in 36 or
150 patients with CVI, MPFF 500mg twice daily
for 2 months significantly decreased ankle or calf
circumference,[69,70,72] improved many symptoms
of CVI (e.g. sensation of heaviness or swelling)[69,70,72] (table III) and improved plethysmographic parameters.[69,72]
Mean ankle circumference decreased from
baseline by 2.2[72] and 4.6mm[70] at week 4 of
MPFF treatment and 4.1[72] and 7.1mm[70] at week
8 (p < 0.001 vs placebo for both timepoints) in
patients with symptoms of CVI. Mean calf measurements also decreased significantly from baseline with MPFF compared with placebo (table
III);[70,72] reductions of 3.8mm at week 4 (p = 0.05)
and 5.7mm at week 8 (p < 0.001) of MPFF treatment were shown in the trial by Gilly et al.[70]
There was a significant correlation between the
improvements in the symptom score of sensation
of swelling and decrease in ankle circumference
between the beginning and end of 2 months’ treatment with MPFF.[70]
Improvements in venous haemodynamics indicated that MPFF increased venous tone in the study
by Chassignolle et al. that also evaluated plethysmographic parameters of venous haemodynamics.[69,72] MPFF significantly decreased venous
capacitance at 50 mm Hg, venous distensibility at
40, 50 and 60mm Hg, total time of venous emptying and the emptying of the final 50% (considered
the active phase of venous outflow) compared with
placebo (p < 0.001 for all).[69]
Table III. Efficacy of oral micronised purified flavonoid fraction (MPFF) in patients (pts) with symptoms of chronic venous insufficiency.
Summary of the results of three randomised, double-blind, placebo-controlled, 2-month trials in which MPFF 500mg twice daily was compared
with twice-daily placebo (PL) or nonmicronised diosmin (DIO) 300mg three times daily.
Reference
Comparisons with PL
Chassignolle et al.[69]
Gilly et al.[70]
Regimen (no. of
enrolled/evaluable pts
MPFF (18) PL (18)
MPFF (76) PL (74)
Changes in clinical response measures
functional
discomfort
nocturnal heat
pain
cramps
sensation
+++
+++
+
+
+
Comparison with DIO
Cospite, M. et al.[71]
MPFF (43) DIO (45)
NS
+
NS = not significant; + p < 0.05, ++ p < 0.01, +++ p < 0.001 MPFF vs comparator.
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Decrease in
circumference
ankle
calf
leg
heaviness
swelling
sensation
+
+
+++
+++
+++
+++
+++
+++
+
+
NS
+++
+++
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
Comparison with Nonmicronised Diosmin
MPFF 500mg twice daily for 2 months improved most clinical symptoms (table III) and decreased venous outflow parameters to a greater
extent than nonmicronised diosmin 300mg three
times daily.[71] The daily dosage of diosmin, the
active principle of MPFF, was equivalent in each
arm of the randomised, double-blind, multicentre,
2-month study in 88 evaluable patients. Statistically significant improvements in all subjective
symptoms were demonstrated by both treatment
groups (p values not reported) at the end of 2
months’ treatment; however, MPFF was more effective than diosmin for the majority of response
measures (table III). Likewise, improvements in
objective parameters (ankle or calf circumferences
[table III] and plethysmographic measurements)
were shown with each treatment but, in general,
were greater with MPFF than with the nonmicronised formulation.
Comparison of Administration Regimens
Two tablets of MPFF 500mg daily for 2 months
was effective in improving the signs and symptoms of CVI compared with baseline values, regardless of the daily administration schedule of the
drug.[73] In a double-blind, multicentre trial in 308
patients with symptoms of CVI, patients were
randomised to one of three comparable groups that
received 2 tablets of MPFF 500mg in the morning
or evening, or MPFF 500mg twice daily. Significant improvements from baseline in functional discomfort were shown by each treatment group during 15–30 days of treatment and continued until
the end of treatment (p < 0.001); the difference was
not significant between the three groups. Leg oedema resolved in 28–43.4% of the 263 patients
with leg oedema at baseline (p < 0.001).[73] Mean
ankle and calf circumference measurements of the
most affected leg decreased significantly compared with baseline values in each treatment group
(p < 0.001); patients receiving 2 tablets of MPFF
500mg in the morning had the greatest decrease in
mean calf measurements (p = 0.025 vs the other
treatment groups).
 Adis International Limited. All rights reserved.
85
4.1.2 Long-Term Treatment
Two tablets of MPFF 500mg daily maintained
its efficacy in the long-term treatment of patients
with symptoms of CVI in two nonblind, multicentre trials of 6-[74] or 12-months’[75] duration.
In the RELIEF trial (n = 4527 intention-to-treat
population), patients receiving 2 tablets of MPFF
500mg daily showed progressive improvements in
the symptoms of CVI, which were parallelled by
improvements from more severe (CEAP clinical
classes C3 or C4) to less severe (C0–C2) stages of
CVI.[74] At baseline, the proportion of patients
with venous reflux classified as having severe disease was approximately twice as high as the proportion without venous reflux (51.1 vs 25.1%). At
the end of 6-months’ treatment, 37.7% of patients
with venous reflux and 15.7% of patients without
venous reflux had severe disease (p < 0.001 vs
baseline); the proportion of patients with an improvement in CEAP classification was greater in
patients with venous reflux than without venous
reflux (13 vs 9%; p < 0.001). After 6 months, both
patient groups in the per-protocol population (n =
3174) showed significant improvements from
baseline in the study outcome measures (p < 0.012;
table IV).
In the 1-year trial of 2 tablets of MPFF 500mg
daily in 170 evaluable patients, a significant reduction from baseline values in physician-assessed
clinical symptoms (functional discomfort, cramps
and evening oedema; figure 4), ankle and calf circumference, and patient overall assessment of
symptom severity was demonstrated at each 2month evaluation (p < 0.001).[75] The rapid reductions observed during the first 2 months of treatment represented approximately 50% of the total
improvements ultimately observed after 1 year of
treatment; continuing improvements in all parameters, albeit less rapid, were reported at each
timepoint from month 2 to month 12.
Effect on Health-Related Quality of Life
Improvements in the clinical signs and symptoms of CVI with 2 tablets of MPFF 500mg twice
daily were associated with significant improvements in CIVIQ (health-related quality-of-life)
Drugs 2003; 63 (1)
86
Lyseng-Williamson & Perry
Table IV. Efficacy of oral micronised purified flavonoid fraction (MPFF) in patients (pts) with symptoms of chronic venous insufficiency with
or without venous reflux. Changes from baseline values after 6 months’ treatment with 2 tablets of MPFF 500mg daily in the per protocol
population (n = 3174) in the Reflux Assessment and Quality of Life Improvement with Micronised Flavonoids Flavonoids (RELIEF) study[74]
Mean change from baseline
Change from baseline in the % of pts
ankle circumference (mm) pain (points)a
leg heaviness
cramps
swelling sensation
Without venous reflux
–11.5*
–2.47***†††
–55.3**
–57.2**††
–48.4**†
With venous reflux
–11.8*
–2.46***
–38.6**
–47.9**
–36.0**
a
Measured on a 10-point visual analogue scale where 0 indicates no pain and 10 intolerable pain.
* p < 0.012, ** p = 0.001, *** p < 0.0001 vs baseline; † p = 0.007, †† p < 0.001, ††† p < 0.0001 vs pts with venous reflux
4.2 In Patients with Venous Ulcers
The efficacy of MPFF in augmenting the healing of venous ulcers has been evaluated in a double-blind, placebo-controlled, 2-month trial (n =
105)[78] and a nonblind, 6-month trial (n = 140).[79]
In these randomised, multicentre trials, 2 tablets of
MPFF 500mg daily plus standard venous ulcer
management was compared with standard venous
ulcer management (compression therapy plus local
treatment). Patients were included in the trials if
they had a venous leg ulcer for a duration of a least
3 months,[78,79] a systolic pressure index (ankle/arm) >0.8[78] or >0.9.[79] The largest ulcer was
used as the reference ulcer if multiple ulcers were
present.[78] In the placebo-controlled study,[78] patients were stratified according to ulcer size (≤10
or >10cm) [mean diameter of reference ulcer was
5.5 and 5.3cm in the MPFF and placebo groups].
In the nonblind, 6-month trial,[79] ulcers were required have a diameter of 2–10cm; the mean size
 Adis International Limited. All rights reserved.
of ulcer was larger and a greater proportion of patients had an ulcer exceeding 6cm in diameter in
the control group than in the MPFF group (6 vs
5.5cm and 31 vs 43%). Standard venous ulcer management comprised cleaning, compresses, dressings, skin care of the surrounding skin and compression therapy.[78,79] The measures of efficacy
included the proportion of patients with complete
venous ulcer healing (i.e. complete re-epithelisation),[78,79] time to complete healing[78] and the per-
3.0
Severity of symptom (points)
scores in the RELIEF trial.[74] Patients with or
without venous reflux showed significant improvement in CIVIQ global index scores (GIS)
after 2, 4 and 6 months of treatment (p = 0.0001;
figure 5).[74,77] GIS increased throughout the study
period with the largest improvement occurring
during the first 2 months of treatment. In addition,
all domains of CIVIQ (psychological, pain, physical dimension and social functioning) improved
significantly from baseline at each 2-month
timepoint in both patient groups (p = 0.0001). For
the domain of pain, patients without venous reflux
improved to a greater extent than patients with venous reflux (p = 0.0106 at 6 months).[74]
Baseline
Month 2
Month 12
2.5
2.0
1.5
*
1.0
*
*
0.5
*
*
*
0.0
Functional
discomfort
Leg
cramps
Evening
oedema
Fig. 4. Improvement in venous symptoms with 2 tablets of oral
micronised purified flavonoid fraction (MPFF) 500mg daily.
Mean decrease in physician-assessed functional discomfort
(sensation of heaviness or heat, paraesthesia or pain in the lower
limbs), leg cramps (mostly occurring at night) and evening oedema (oedema or swelling of the feet and/or ankles mostly occurring at the end of the day) from baseline with 2 tablets of MPFF
500mg daily in a noncomparative, multicentre, 12-month trial in
170 evaluable patients with functional symptoms of venous insufficiency.[75] Symptoms were assessed on a 4-point scale
where 0 indicated symptoms were absent and 4 indicated symptoms were very intense and very frequent. * p < 0.001 vs baseline.
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
Global index score on CIVIQ (points)
90
80
70
*
*
*
*
*
*
Baseline
Month 2
Month 4
Month 6
60
50
40
30
20
10
0
Patients with
venous reflux
Patients without
venous reflux
Fig. 5. Improvement in health-related quality-of-life scores with
oral micronised purified flavonoid fraction (MPFF). Improvements in the global index score of the ChronIc Venous Insufficiency Questionnaire (CIVIQ) with 2 tablets of MPFF 500mg
daily for 6 months in 3656 evaluable patients with symptoms of
CVI with or without venous reflux in a nonblind, multinational
study.[74,77] CIVIQ scores range from 0–100 where 100 indicates
a very good health-related quality of life. * p = 0.0001 vs baseline.
87
were completely healed in a significantly greater
proportion of patients receiving MPFF plus standard management (n = 35) than in those receiving
standard management alone (n = 25) [60 vs 32%;
p < 0.05]. Ulcers <3cm diameter were completely
healed in 71% of patients receiving MPFF versus
50% of patients in the control group; ulcers >6cm
in diameter were completely healed in 9% of
MPFF recipients and 13.3% of patients in the control group.[79]
Treatment with MPFF for 2 months significantly shortened the time to complete healing of
ulcers ≤10cm in diameter relative to placebo (p =
0.037).[78] The odds ratio for complete healing
with MPFF compared with placebo was similar for
patients with diabetes mellitus and without diabetes mellitus (odds ratios 2.5 and 2.23).
In the 2-month trial, a similar change in ulcer
surface area was shown by the two treatment
groups;[78] however, in the longer nonblind trial,[79]
mean ulcer area was reduced to a significantly
50
4.2.1 Effects on Venous Ulcer Healing
The addition of 2 tablets of MPFF 500mg daily
to standard venous ulcer management accelerated
the complete healing of venous leg ulcers ≤10cm
in diameter (figure 6).[78,79] MPFF 500mg twice
daily plus standard management completely
healed venous ulcers ≤10cm in diameter in 19%
more patients than standard management plus placebo or standard management alone in a doubleblind, 2-month trial (32 vs 13%; p = 0.028)[78] and
a nonblind, 6-month trial (46.5 vs 27.5%; p <
0.05).[79] Ulcers >10cm in diameter did not completely heal in either the active-treatment or placebo group during the 2-month trial.[78] In subgroup analysis by ulcer size in the 6-month trial,[79]
ulcers measuring between 3 and 6cm in diameter
 Adis International Limited. All rights reserved.
*
Patients with complete ulcer healing (%)
centage of ulcer surface area healed.[78,79] In addition, the retrospective cost-effectiveness of MPFF
in the treatment of venous ulcers in patients with
CVI over 6 months was assessed in the nonblind
trial.[79]
45
40
35
*
30
25
20
15
10
5
0
MPFF + SM
(n = 44)
PL + SM
(n = 47)
2-month study
MPFF + SM
(n = 71)
SM alone
(n = 69)
6-month study
Fig. 6. Efficacy of oral micronised purified flavonoid fraction
(MPFF) plus standard venous ulcer management (SM) in the
complete healing of venous ulcers ≤10cm in diameter. Patients
with venous ulcers received SM (compression therapy plus local
treatment) plus 2 tablets of MPFF 500mg daily or placebo (PL)
in a randomised, double-blind, multicentre, 2-month trial,[78] or
SM plus 2 tablets of MPFF 500mg daily or SM alone in a
randomised, nonblind, multicentre, 6-month trial.[79] *p < 0.05.
Drugs 2003; 63 (1)
88
Lyseng-Williamson & Perry
greater extent in patients receiving MPFF plus
standard management than in patients receiving
standard management alone (80 vs 65%; p < 0.05).
In comparison with standard management alone in
the 6-month trial,[79] the addition of MPFF to
standard management significantly reduced discomfort related to ulcer (64.8 vs 38.3% of patients;
p < 0.01), but no between-group differences were
seen in other secondary clinical symptom endpoints (pain, heavy legs or night cramps).
4.2.2 Cost-Effectiveness
MPFF plus standard venous ulcer management
was cost-effective in the treatment of venous ulcers
in the nonblind, 6-month study by Gliñski et al.[79]
Based on the cost per healed ulcer over 6 months,
the MPFF group had a lower cost-effectiveness ratio than the control group (1026 euros [EUR] vs
EUR1872) in a retrospective pharmacoeconomic
analysis (year of costing 1998).[79] The MPFF
group had lower costs per patient over 6 months
than the control group; the cost of direct medical
care, drugs and dressings, laboratory tests, Doppler
examination and home health care was EUR39
lower per patient and the cost of hospitalisation
was EUR128 lower per patient. Because there were
no statistically differences in the number of adverse events between the two groups, costs for adverse events were not included.[79]
4.3 In Patients with Haemorrhoids
Several randomised, double-blind, placebocontrolled trials have evaluated the efficacy of oral
MPFF[23,80,81] in the management of acute internal
haemorrhoids. MPFF plus fibre was compared
with fibre alone or fibre plus rubber band ligation
in the treatment of bleeding nonprolapsed haemorrhoids in a randomised, nonblind trial.[82] A noncomparative trial assessed the use of MPFF in the
management of acute haemorrhoids associated
with pregnancy in patients with amenorrhoea of
>28 weeks and acute haemorrhoidal disease of ≤7
days’ duration.[83]
Patients included in the trials had a history of
haemorrhoidal disease (mainly grade 1 or 2 internal haemorrhoids), which was confirmed by clini Adis International Limited. All rights reserved.
cal examination including proctoscopy.[23,80-83] In
the double-blind, placebo-controlled trials, patients had an acute haemorrhoidal attack with [81]
or without rectal bleeding[80] for less than[81] or no
more than 3 days,[80] or an acute episode of haemorrhoids within the previous 2 months.[23] In the
second phase of the trial by Misra et al.,[81] treatment was continued for an additional 83 days in the
patients whose bleeding had ceased by the end of
the initial 7-day phase.
Among exclusion criteria in the trials were external thrombosed haemorrhoids,[23,80] previous
haemorrhoidectomy,[23] haemorrhoids requiring
surgery,[23,80,83] prior laser treatment for haemorrhoids,[81,83] recent or current treatment with a
phlebotropic, anticoagulant or anti-inflammatory
agent.[23,80,81,83] In one trial, certain topical or systemic analgesics were permitted.[80]
In the treatment of acute symptoms, MPFF
500mg was generally given orally as a loading dosage of 3 tablets twice daily for 4 days then 2 tablets
twice daily for 3 days;[80,81,83] in long-term treatment, the dosage was 500mg twice daily.[23,81]
The efficacy of MPFF in the management of
haemorrhoids was evaluated by changes in number, frequency and duration of acute attacks,[23,81,82] and/or changes in the objective signs
(e.g. swelling, congestion, bleeding, exudation and
prolapse) or subjective symptoms (e.g. pain, pruritus, tenesmus and mucous discharge) of haemorrhoids.[23,80,83]
A randomised, nonblind trial evaluated the efficacy of MPFF in decreasing the proportion of patients with secondary bleeding after elective
haemorrhoidectomy.[84] Secondary bleeding, the
major complication of this procedure, occurs in
3.3–6.7% of patients ≈7–14 days after surgery.[84]
4.3.1 Comparison with Placebo
Treatment of Acute Symptoms
Significant improvements in the duration and/or
intensity of symptoms of acute internal haemorrhoids were reported with MPFF 500mg (3 tablets
twice daily for 4 days then 2 tablets twice daily for
3 days) in two randomised, double-blind, placebocontrolled trials in 100 patients (table V).[80,81]
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
Improvements in the individual symptoms of
acute haemorrhoids (bleeding, anal discomfort,
pain, anal discharge, proctitis) and overall patientevaluated symptoms were reported in both patient
groups in the trial by Cospite et al.;[80] improvements were significantly greater with MPFF than
with placebo (p ≤ 0.006). The greater overall improvement in symptoms with MPFF than with
placebo was evident by day 2 of treatment and
increased during days 3–7 (p < 0.001 at all
timepoints). After the first few days of treatment,
MPFF recipients used authorised systemic (glafenine) and topical (lidocaine 5%) analgesics to a significantly lesser extent than placebo recipients (p
< 0.05 on day 3 to day 7 of treatment).
Treatment of Chronic Symptoms
Long-term treatment with MPFF 500mg twice
daily for 60[23] or 83 days[81] reduced the risk of
relapse of acute haemorrhoidal symptoms in two
randomised, double-blind, placebo-controlled trials in 120[23] and 100 patients[81], respectively,
with chronic symptoms of haemorrhoids. Relapses
of bleeding occurred in 18 or 36% fewer patients
receiving MPFF than placebo (p < 0.05) in the 83day preventative phase of the 3-month trial[81] or
in the 2-month trial.[23] In the 2-month trial, the
mean number of relapses per patients and the duration and severity of acute attacks were significantly decreased with MPFF compared with placebo (p < 0.01; table VI).[23]
Compared with placebo, MPFF 500mg twice
daily for 2 months also effectively treated the
symptoms and signs of chronic haemorrhoids (table VI).[23] After 2 months of treatment, overall
89
symptom and sign scores as well as scores for individual symptoms (pain, pruritus, bleeding, tenesmus and mucous discharge) and signs (bleeding on examination, oedema and erythema) were
significantly less in the MPFF group than in the
placebo group (p < 0.01).
4.3.2 MPFF plus Fibre in Comparative Trials
Treatment with MPFF plus fibre resolved
bleeding from nonprolapsed internal haemorrhoids 64% more rapidly than fibre alone (p = 0.03)
in a randomised, nonblind trial; the time to resolution was not significantly different between the
MPFF plus fibre group and the rubber band ligation plus fibre group (table VII).[82] The number of
recurrences of bleeding during 3 months of intervention plus 3 months of observation without intervention was not significantly different between
any of the three treatment groups (fibre [ispaghula
husk 3.5g twice daily for 3 months], fibre plus 3
tablets of MPFF 500mg twice daily for 5 days then
2 tablets twice daily for 3 weeks, or fibre plus rubber band ligation of three internal haemorrhoids).
4.3.3 In Pregnant Patients
Symptoms of acute haemorrhoids in 50 pregnant patients improved with short-term MPFF
treatment in a noncomparative trial.[83] In the first
phase of the trial, patients received 3 tablets of
MPFF 500mg twice daily for 4 days, then 2 tablets
twice daily for 3 days; in the antenatal and 30-day
postnatal periods, patients received MPFF 500mg
twice daily. After a median of 4 days in the initial
phase, overall haemorrhoidal symptom scores
improved from baseline by 66% (95% CI 79.1–
52.9).[83] After treatment with 2 tablets of MPFF
Table V. Efficacy of oral micronised purified flavonoid fraction (MPFF) compared with placebo (PL) in the treatment of acute internal
haemorrhoids. Results of two randomised, double-blind studies in which patients with acute bleeding from internal haemorrhoids received
3 tablets of MPFF 500mg twice daily for 4 days then 2 tablets twice daily for 3 days
Reference (no. of pts)
Parameter
MPFF
PL
Cospite et al.[80] (100)
Decrease in attack durationa (% of pts)
77.5**
24.5
Misra et al.
a
[81]
(100)
Decrease in attack intensitya (% of pts)
89.8**
38.8
Cessation of bleeding on third day of treatment (% of pts)
80*
38
Mean duration of bleeding (days)
4.9*
7.0
Compared with the duration of attacks in the past year.
* p < 0.01, ** p < 0.001 vs PL.
 Adis International Limited. All rights reserved.
Drugs 2003; 63 (1)
90
Lyseng-Williamson & Perry
Table VI. Efficacy of long-term oral micronised purified flavonoid fraction (MPFF) 500mg twice daily compared with placebo (PL) in the
treatment of internal haemorrhoids. Results of a randomised, double-blind, 2-month study in patients (pts) with an acute attack of internal
haemorrhoids during the previous 2 months[23]
Regimen (no. of
evaluable pts)
Acute relapse
pts with at least 1
relapse (%)
mean no. of
relapses
duration
(days)
severityc
Overall chronic
symptom scorea
Overall chronic
sign scoreb
baseline
endpoint
baseline
endpoint
MPFF (58)
40*
0.6**
2.6**
1.1**
6.6
1.1**
4.9
0.9**
PL (55)
76
2.1
4.6
1.6
6.1
4.0
4.5
2.9
a
The total of scores for pain, pruritus, bleeding, tenesmus and mucous discharge. Each symptom was assessed on a scale of 0 to 3; maximum overall score is 15. A decrease in score is consistent with improvement.
b
The total of scores for bleeding on examination, oedema and erythema. Each symptom was assessed on a scale of 0 to 3; maximum
overall score is 9. A decrease in score is consistent with improvement.
c
On a scale of 1 to 3 where a lower score is consistent with less severity.
* p < 0.05, ** p < 0.01 vs placebo.
500mg twice daily for a further 3 days, there was
a significant reduction from baseline in median
symptom scores for bleeding, pain, rectal discomfort and rectal exudation (p < 0.05). Although
MPFF reduced the proportion of patients with inflammation at proctoscopy by 46% (p < 0.001), the
proportion of patients with prolapse or thrombosis
was not significantly reduced.
In the antenatal period, maintenance treatment
with MPFF 500mg twice daily in 44 patients significantly reduced both the frequency and duration
of relapses of symptoms of acute haemorrhoids
compared with baseline values (history during the
current pregnancy and the year preceding it) [p <
Table VII. Efficacy of oral micronised purified flavonoid fraction
(MPFF) plus fibre in the management of haemorrhoidal bleeding.
Results of a randomised, nonblind trial in which patients (pts) with
bleeding nonprolapsed haemorrhoids received MPFF plus fibre,
fibre alone or rubber band ligation (RBL) plus fibre.[82]
Treatment
No. of pts Haemorrhoidal bleeding
no. of days to
stop (mean)
recurrencea
(% of pts)
MPFFb plus fibrec
39
Fibrec
66
10.6
12
RBLd plus fibrec
57
5.6
21
3.9*
5.1
a
During 3 months of intervention plus 3 months of observation
without intervention.
b
Three tablets of MPFF 500mg twice daily for 5 days then 2 tablets twice daily for 3 weeks.
c
Ispaghula husk 3.5g twice daily for 3 months.
d
RBL of three internal haemorrhoids.
* p = 0.043 vs fibre.
 Adis International Limited. All rights reserved.
0.001].[83] During the 30 days of postnatal maintenance treatment (n = 41), there was a significant
reduction in the duration of relapses (p < 0.05).
4.3.4 To Reduce Bleeding After
Haemorrhoidectomy
MPFF reduced the risk of secondary bleeding
after elective haemorrhoidectomy performed with
a standardised diathermy excision method by a single surgeon.[84] Of 114 patients receiving 2 tablets
of MPFF 500mg three times daily for 3 days then
1 tablet three times daily for 4 days, one (0.9%)
patient had secondary haemorrhage compared with
seven (6.1%) of 114 patients in the control group
(p = 0.03) in a randomised, nonblind trial. In the
control group, the mean time that bleeding occurred after surgery was 11.3 days (range 6–15
days); the patient in the MPFF group bled 14 days
after surgery. Patients in both groups had three
haemorrhoids excised without ligation of the pedicles, received routine postoperative pain relief,
bulking agents and laxatives, and had similar postoperative hospital stays (mean 2.1 days for all patients).
5. Tolerability
MPFF has been well tolerated by patients participating in clinical trials, with most reported
events being mild and transitory.[69-71,73,75,78,80-85]
In an analysis of several comparative and noncomparative clinical trials in 2850 patients with
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
CVI or haemorrhoids who received 2 tablets of
MPFF 500mg daily for 6 weeks to 1 year,[85] gastrointestinal adverse events (e.g. abdominal pain,
gastric discomfort, epigastric pain, nausea, dyspepsia, vomiting and diarrhoea) in 6.9% of patients
and autonomic adverse events (e.g. insomnia,
drowsiness, vertigo, headache, tiredness, anxiety,
cramps, palpitations and hypotension) in 1.7% of
patients were the most frequently reported events.
In these trials, the proportion of patients with an
adverse event was similar in patients receiving
MPFF (10%) to that in 225 patients receiving placebo (13.9%). Adverse events were similar in nature and incidence between these patient groups.
The rate of discontinuation because of adverse
events (primarily of gastrointestinal origin) were
comparable among patients receiving 2 tablets of
MPFF 500mg daily or placebo (1.1 vs 3.2%).[85]
In this analysis,[85] the incidence of adverse
events was not significantly different in patients
aged ≥70 years or with concomitant diseases (i.e.
hypertension, atherosclerosis, diabetes mellitus,
neurological/psychiatric disease or alcoholism) to
that in the total population group. In addition,
MPFF did not appear to interact with the drugs
used to treat these concomitant diseases.
The incidence of adverse events did not increase with long-term treatment with 2 tablets of
MPFF 500mg daily. In a 2-month placebo-controlled trial in patients with CVI,[70] 12% of 74 MPFF
and 16% of 76 placebo recipients experienced adverse events (mostly of a gastrointestinal nature).
In comparison, adverse events were documented
by 20 of 215 patients (9%) in a 1-year noncomparative trial.[75]
Increasing the dosage of MPFF 500mg to 4–6
tablets daily for 7 days did not change the nature
or incidence of adverse events.[80,81,84] In placebocontrolled trials of MPFF 500mg (6 tablets daily
for 4 days then 4 tablets daily for 3 days; n = 100
in each study) in the treatment of acute haemorrhoids (section 4.3.1),[80,81] the incidence of adverse events was similar in MPFF and placebo recipients (2–8% vs 0–6%); gastrointestinal adverse
 Adis International Limited. All rights reserved.
91
events were the most frequently reported in both
groups.
Treatment with MPFF did not modify blood pressure[70,75,80,81] or laboratory parameters.[70,73,75,81]
Systolic or diastolic blood pressure and laboratory
values did not change during treatment with 2 tablets of MPFF 500mg daily for 1 year in a clinical
trial (n = 215) that monitored these parameters every 4 months.[75] Laboratory values (e.g. red blood
cells, leukocytes, haemoglobin, hepatic enzymes,
blood urea, blood glucose and lipids) remained
within normal physiological ranges. Although
there was a significant decrease in creatinine levels
between the beginning and end of treatment (87.7
to 84.0 µmol/L; p < 0.05), these values remained
within the normal range.
In a study in 50 pregnant patients with acute
haemorrhoids (section 4.3.3),[83] nausea or diarrhoea occurred in seven patients and led to the
withdrawal from the study of two patients during
the initial phase of the trial. There was no significant change in haemodynamic and biochemical
parameters during antenatal treatment, and values
were within the normal range at the end of the
study. The median antenatal maintenance treatment phase was 8 weeks (n = 44) and the postnatal
maintenance treatment phase was 30 days (n = 41).
Ultrasonography did not detect any fetal abnormality (n = 44); a malformation was detected at
birth in one infant (single umbilical artery) and
there was one intrauterine death (true knot in cord
and cord around the neck). All evaluable infants (n
= 39) were mature at birth (median maturity 39
weeks) and the median weight of the infants
(2.9kg) was normal for the Indian population.
6. Dosage and Administration
MPFF is administered orally and is available as
500mg tablets.[27] It is generally indicated for the
treatment of organic or idiopathic CVI of the lower
limbs with symptoms of heavy legs, pain or nocturnal cramps, and acute haemorrhoidal attacks or
chronic haemorrhoids.
MPFF is approved for use in over 100 countries
including nine countries in the EU (Austria, BelDrugs 2003; 63 (1)
92
Lyseng-Williamson & Perry
gium, Denmark, France, Greece, Italy, Luxembourg, Portugal and Spain) and 20 other European
countries;[86] dosage recommendations and approved indications may vary from country to country.[68] In general, the recommended dosage of
MPFF 500mg in CVI is 2 tablets daily (as a single
dose in the morning or evening or 1 tablet twice
daily), in acute haemorrhoidal attacks 2 tablets
three times daily for 4 days followed by 2 tablets
twice daily for 3 days, and in chronic haemorrhoids
2 tablets daily.[27,87]
There are no documented drug interactions with
MPFF.[68] Caution is recommended when administering MPFF to patients who are breast feeding
because of the absence of data concerning the diffusion of MPFF into breast milk. No adverse effects have been reported to date when MPFF was
administered during pregnancy.
MPFF is associated with an incidence of adverse events similar to that seen with placebo; the
majority of adverse events are mild and transitory
(section 5). The most common adverse events with
MPFF are gastrointestinal (6.9% of patients in clinical trials) and autonomic (1.7%). Increasing the
length of treatment or the dosage does not appear
to change the nature or incidence of adverse events.
MPFF does not modify blood pressure or laboratory parameters or interact with concomitant medications. Moreover, MPFF was well tolerated in a
noncomparative study in 50 pregnant patients with
haemorrhoids. The following sections discuss the
standard management and indication for the use of
oral MPFF in the treatment of CVI, venous ulcers
and acute or chronic internal haemorrhoids.
7. Place of Micronised Purified
Flavonoid Fraction in the Management
of CVI, Venous Ulcers and
Haemorrhoids
In recent guidelines on the treatment of
CVI,[2,90] the use of phlebotropic agents is indicated to treat oedema and the symptoms of CVI
(e.g. oedema, fatigue, nocturnal cramps and heaviness) in any stage of the disease. In the more advanced stages of CVI, phlebotropics are also used
in conjunction with sclerotherapy, surgery and/or
compression therapy,[2,88] or as an alternative treatment when surgery is not indicated or is unfeasible[2] or when patients are unwilling or unable to
use compression therapy (elastic stockings or compression bandages).[90] These recommendations
were supported by clinical trials of phlebotropic
drugs including MPFF, which has been extensively
evaluated for use in patients with CVI (section
4.1).[2]
MPFF 500mg twice daily significantly reduces
oedema and several of the subjective symptoms of
CVI (functional discomfort, pain or sensation of
heat/burning, heaviness or swelling) compared
with placebo according to data from two
randomised, double-blind, placebo-controlled, 2month trials (section 4.1.1).[69,70] Significantly
greater decreases in ankle and calf circumferences,
and venous distensibility and emptying time are
demonstrated with MPFF than with placebo.
Phlebotropic agents act on various venous
pathophysiological processes that produce the
clinical manifestations of CVI, venous ulcers or
haemorrhoids (section 2).[2,4,24,88,89] Phlebotropics
are classified as benzopyrone derivatives (e.g. coumarin and flavonoids such as MPFF and hydroxyethylrutosides), saponins (e.g. escin [horsechestnut extract]), other plant extracts (e.g.
bilberry or grape pip extracts) and synthetic substances (e.g. calcium dobesilate).[4,88,90]
MPFF is a well established phlebotropic and
vasoprotective agent that has been intensively investigated in well designed clinical trials (section
4). It has been shown to increase venous tone (section 2.1), protect the microcirculation from inflammatory processes (section 2.2), and improve lymphatic drainage (section 2.3). Micronisation of the
particle size of diosmin to <2µm improves the oral
absorption and bioavailability of diosmin compared with that of nonmicronised diosmin (section
3.1).
 Adis International Limited. All rights reserved.
7.1 CVI
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
MPFF maintains its efficacy in the long-term
treatment of CVI as shown in two 6- or 12- month
trials of 2 tablets of MPFF 500mg daily (section
4.1.2). In the large 6-month RELIEF trial, the improvement in the symptoms of CVI was paralleled
by a significant change in CEAP classification from
a more severe to a less severe disease stage in both
patients with or without venous reflux (p <
0.001).[74] Moreover, both groups of patients also
showed a significant improvement in their healthrelated quality of life as measured by the CIVIQ
GIS (section 4.1.2). Most of the improvements in
symptoms or GIS occurred during the first 2
months of treatment; however, symptoms continued to improve at each timepoint in the long-term
trials.
Micronisation of diosmin improved its efficacy
compared with the nonmicronised formulation
(section 4.1.1). Two tablets of MPFF 500mg daily
for 2 months was more effective than the same
nominal dosage of nonmicronised diosmin in improving most of the subjective symptoms and objective parameters (ankle and calf circumferences
and plethysmographic measures) in patients with
CVI. Improvements were shown with each treatment, but generally were significantly greater with
MPFF than nonmicronised diosmin (p < 0.05).
Although not as extensively studied as MPFF,
other phlebotropic agents are also effective in the
treatment of oedema and symptoms of CVI.[2,4,88,90]
Phlebotropic agents that were more effective in the
treatment of CVI than placebo in randomised, double-blind, placebo-controlled clinical trials of 3–
26 weeks’ duration include: butcher’s broom (Ruscus aceuleatus) 72–75 mg/day,[91] calcium
dobesilate 1500 mg/day,[92] escin (horse-chestnut
extract) 100–150 mg/day (reviewed by Pittler and
Ernst[93]) and hydroxyethylrutosides (reviewed by
Wadsworth and Faulds[94]). According to Ramelet
et al.,[88] phlebotropics are all generally well tolerated with adverse events occurring in ≈5% of patients. Adverse events include vertigo, headache,
and flatulence and are seldom severe; however,
hepatitis has been very rarely reported in patients
 Adis International Limited. All rights reserved.
93
taking coumarols or benzarone, and skin rashes
may occur with tibenoside and naftazone.[88]
In patients in the more advanced stages of CVI,
MPFF may be used as the first-line treatment for
oedema and the symptoms of CVI, as well as in conjunction with compression therapy, sclerotherapy
and/or surgery. The function of compression therapy in the treatment of CVI is to control oedema
and counteract the effects of venous hypertension.[1,2,4] Compression reduces the superficial venous pressure and the leakage of fluid to the microcirculation and improves the venous return by
assisting the muscle pump in the lower leg. The
individual requirements of the patient and the severity of disease dictate the type and method of
compression used.[2] Patients should continue to
use compression therapy after surgery or
sclerotherapy for varicose veins;[2] the use of compression stockings for 1 year significantly reduced
the postoperative recurrence of varicose veins
compared with no compression therapy in a nonblind trial (p < 0.01).[95]
Sclerotherapy, the injection of a chemical to
obliterate varicose veins, is performed with various sclerosing substances at varying concentrations depending on the indication.[2,4] Although
initially the vein is obliterated in more than 80%
of cases, recanalisation and recurrence frequently
occur.[2] In general, sclerotherapy is not an alternative to surgery and is indicated for a variety of
conditions such as telangiectasia, varices 1–3mm
in diameter, varices in which surgery is not advisable and varicose veins around an ulcer.
Surgical treatment for CVI depends on the
symptoms, pathology and/or complications of the
varices.[2,4] Although CVI is likely to be progressive, and new varicose veins may eventually appear, the goals of varicose vein surgery are relief
of the symptoms and prevention and treatment of
complications. Many different types of surgery
(e.g. ablative surgery, ligation of saphenofemoral
junction, perforator ligation or endovascular surgery) may be performed as indicated for specific
conditions.
Drugs 2003; 63 (1)
94
Lyseng-Williamson & Perry
7.2 Venous Ulcers
Venous ulcers are the most severe manifestation
of CVI, are slow to heal, have a tendency to recur[2,96,97] and are costly to treat.[4,98] The goal of
treatment is to not only heal the ulcer but to also
prevent its recurrence. In addition to macrovascular haemodynamics, venous ulcer formation involves the microcirculation and endothelium;
therefore, its treatment should also consider all of
these pathophysiological mechanisms.[2,12]
According to recent guidelines,[2,90] systemic
pharmacological treatment targeting one or more
of the factors identified in the pathophysiology of
venous ulcers (section 2) may be used as an adjuvant to standard (compression and local therapy)
venous ulcer management. Although the efficacy
of supportive pharmacological therapy has been
debatable because of methodological limitations
in past trials, recent trials of MPFF (section
4.2.1)[78,79] in combination with standard management have overcome these limitations[2] and fulfil
the recommended trial criteria.[99]
MPFF 500mg twice daily in combination with
standard management accelerates the complete
healing of venous leg ulcers according to data from
clinical trials (section 4.2.1). The mechanism of
action of MPFF on this effect may be attributable
to its protective effects on the microcirculation and
the decrease in ICAM-1 and VCAM levels resulting in a decrease in leukocyte trapping and activation (section 2.2).[29] Venous leg ulcers with a
diameter ≤10cm were completely healed in significantly more patients receiving 2 tablets of MPFF
500mg daily in combination with standard management for 2 or 6 months than in patients receiving standard management alone or with placebo (p
< 0.05; section 4.2.1).[78,79] In the 6-month trial,
MPFF significantly reduced mean ulcer area (80 vs
65%; p < 0.05) and discomfort related to ulcer
(64.8 vs 38.3%; p < 0.01) compared with the control group.[79]
Moreover, MPFF is a cost-effective addition to
the standard management of venous ulcers according to a retrospective pharmacoeconomic analysis
of the 6-month trial (section 4.2.2). The cost-effec Adis International Limited. All rights reserved.
tiveness ratio (based on the cost per healed ulcer
over 6 months) was lower in the MPFF group than
in the control group (EUR1026 vs EUR1872; year
of costing 1998).[79] The costs of direct medical
care (e.g. drugs, dressings and home health care)
and hospitalisation were both higher in the control
group than in the MPFF group.
Other systemic drugs that have been used in the
treatment of venous leg ulcers include pentoxifylline, aspirin, profibrionolytic agents (i.e. stanozolol
and defibrotide), hydroxyethylrutosides and intravenous prostaglandin E1.[2,90,98] The Guidelines of
the American Venous Forum[90] conclude that, of
the systemic drugs studied in the treatment of venous ulcers, only MPFF and pentoxifylline have
some efficacy and that aspirin, ifetroban, stanozolol, and hydroxyethylrutosides are ineffective in
the treatment of venous ulcers.
In two randomised, double-blind, placebo-controlled, 6-month clinical trials (n = 129[100] and
80[101]), pentoxifylline plus compression therapy
accelerated the healing of venous leg ulcers compared with placebo. The efficacy shown by pentoxifylline probably results from its inhibitory action on the production of pro-inflammatory
cytokines.[100] Pentoxifylline 400 or 800mg three
times daily healed venous ulcers more rapidly than
placebo (83, 71 and 100 days, respectively);[100]
the between-group difference in healing time was
significant only for the higher dosage of pentoxifylline (p = 0.043 vs placebo). However, in the
other trial,[101] pentoxifylline 400mg three times
daily healed a significantly greater proportion of
venous ulcers than placebo (64 vs 34%; p = 0.03).
The efficacy of pentoxifylline in healing ulcers has
not been compared with that of MPFF.
In a small (n = 42), randomised, double-blind,
placebo-controlled trial, intravenous prostaglandin
E1 60 µg/day for up to 6 weeks was significantly
more effective than placebo in improving ulcer status (p < 0.001) and completely healing ulcers (40
vs 9% of patients; p-value not reported);[102] however, its routine use is hampered by its route of
administration and acquisition cost.[78]
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
Graduated compression therapy improves the
rate of ulcer healing and decreases the rate of recurrence in patients compliant with compression
therapy.[103-105] The addition of MPFF to compression therapy may accelerate the healing of venous
leg ulcers (section 4.2.1). The mechanism of action
of compression therapy is not completely known
and involves many components.[105,106] These include a possible improvement in venous hypertension and microcirculatory haemodynamics and a
decrease in the superficial venous pressure, reducing the leakage of fluid and macromolecules,
which decreases oedema.[2,12,105] High compression is more effective than low compression but
cannot be used in the presence of significant arterial disease. Various types of high compression
systems (e.g. multilayer bandaging, short stretch
bandages and Unna’s boot) have not been shown
to have clear differences in effectiveness.[103] Importantly, elastic compression stockings must be
continued to be used following ulcer healing to
prevent the recurrence of ulcers;[105] patient noncompliance with compression is consistently associated with ulcer persistence or recurrence.[104,105,107]
In addition, patients should also be advised to
maintain their ideal bodyweight, have two to three
30-minute walks on flat ground each day, avoid
standing for long periods, occasionally elevate
their legs higher than their heart during the day,
and sleep with their legs slightly elevated.[2]
Venous ulcers may be treated with topical treatments to keep the lesion clean, preserve the microenvironment, protect the lesion from infectious
agents and stimulate cell repair.[2,4,12] A wide variety of topical treatments (e.g. occlusive or semiocclusive medications, absorbents, alginates, debriding agents and collagens) are available as
pastes, granules, foams or gels; however, their efficacy has seldom been assessed in well controlled
clinical trials.[4] None of these topical treatments
are ideal; the decision of which products to use
should take into account the stage of the disease,
the presence of dead tissue, exudate or infection,
and the condition of the surrounding skin.[2] Because of the increased susceptibility to contact der Adis International Limited. All rights reserved.
95
matitis with topical antibacterials, systemic antibacterials are generally used in the treatment of
bacterially infected ulcers;[2,12,90] importantly, systemic antibacterials should not be used in the management of uncomplicated venous ulcer.[12,90]
Surgery or sclerotherapy should be considered
as a complement to compression therapy with the
objective of correcting haemodynamic changes
and/or covering the ulcer surface with grafted
skin.[2] These measures are most effective in patients with ulcers of the superficial venous system.
7.3 Haemorrhoids
Medical treatments, such as MPFF and/or dietary fibre, are considered first-line therapy to control internal haemorrhoidal symptoms.[24,25]
Haemorrhoidal disease is a benign condition and
the anal cushions play an important role in faecal
continence;[21] therefore, the goal of treatment of
haemorrhoids is to relieve the symptoms and not
to correct the anatomy.[22,24,25] Successful treatment requires correct identification of the condition and an understanding of the underlying pathology; many other anorectal conditions have
similar symptoms and the terms haemorrhoids and
piles have been misused by both laypeople and
medical personnel.[22,25]
According to a recent guideline,[24] MPFF may
be used as a short-term treatment for the symptoms
(pain, prolapse and/or bleeding) of internal haemorrhoids. MPFF has been studied in the management of internal haemorrhoids because of its
phlebotropic activity, protective effect on the capillaries and anti-inflammatory effects (section
2).[24,80] The efficacy of MPFF in alleviating acute
internal haemorrhoidal attacks and/or preventing
further attacks has been studied in several clinical
trials (section 4.3).
As shown in data from trials using varying dosages and study lengths, MPFF effectively alleviates the symptoms of acute internal haemorrhoidal
attacks (section 4.3.1). MPFF 500mg (6 tablets
daily for 4 days then 4 tablets daily for 3 days)
reduces the duration and/or intensity of symptoms
of acute haemorrhoids (e.g. bleeding, pain and anal
Drugs 2003; 63 (1)
96
discharge) relative to placebo (section 4.3.1).
Moreover, patients receiving MPFF use less systemic and topical anaesthetics after the first few
days of treatment than patients receiving placebo.
Bleeding from nonprolapsed internal haemorrhoids resolves more quickly with MPFF 500mg
(3 tablets twice daily for 5 days, then 2 tablets twice
daily for 3 weeks) plus fibre than with fibre alone,
but not significantly more rapidly than with rubber
band ligation plus fibre (section 4.3.2). In a noncomparative trial in pregnant women (section
4.3.3), MPFF 500mg (6 tablets daily for 4 days,
then 4 tablets daily for 3 days) improved the overall
symptoms of haemorrhoids from baseline by 66%.
The frequency and duration of relapses of acute
internal haemorrhoidal symptoms are reduced with
long-term treatment with 2 tablets of MPFF 500mg
daily according to data from clinical trials (section
4.3.1 and 4.3.3). Relative to placebo, MPFF prevents relapses of bleeding in 18–36% more patients, reduces the duration and severity of acute
attacks, and reduces the signs and symptoms of
chronic haemorrhoids (section 4.3.1). Compared
with the patient’s history during the current pregnancy and the year preceding it, maintenance treatment with MPFF reduces the frequency and duration of relapses of acute haemorrhoids during the
antenatal period in pregnant patients (section
4.3.3); in the 30-day postnatal period, maintenance
treatment reduces the duration, but not the frequency, of relapses.
Dietary modifications and high fibre bulking
agents are also recommended as initial treatments
for haemorrhoids.[22,24,25,108] These agents promote soft, but formed, regular bowel movements,
which may reduce shear forces during defecation.
Supplementation with fibre alleviated the symptoms of haemorrhoidal disease compared with a
control group[109] or placebo[110] in clinical trials.
Despite the efficacy of dietary fibre in reducing the
symptoms, constipation has not been conclusively
shown to be a cause of haemorrhoids.[25] Although
not studied extensively in clinical trials, sitz baths
(which may promote the relaxation of the internal
 Adis International Limited. All rights reserved.
Lyseng-Williamson & Perry
anal sphincter[111]) and proper anal hygiene may
also help to alleviate symptoms.[22]
Although corticosteroids or anaesthetics (e.g.
5% lidocaine) administered topically are widely
used to treat the irritation and pruritus associated
with haemorrhoids, their efficacy has not been
demonstrated in clinical trials.[22,24] Prolonged use
of topical corticosteroids is potentially harmful and
should be advised against.[24,108]
Patients who continue to have symptoms of
acute internal haemorrhoids while receiving medical treatment may require instrumental or surgical
treatment.[22,24,25,108] The purpose of the minimally
invasive instrumental approaches is to fix the sliding anal tissue back onto the muscle wall by initiating tissue fibrosis;[25] the choice of treatment is
often determined by the equipment availability and
user familiarity.[22] The instrumental treatment of
grade 1–2 acute internal haemorrhoids includes injections of sclerosing agents, which directly initiate tissue fibrosis, and laser treatment, infrared
photocoagulation, cryotherapy or electrocoagulation, which cause tissue destruction leading to scarring and fibrosis.[22,24,25,108] Grade 1–3 internal
haemorrhoids may be treated with rubber band ligation which removes excess tissue.
Surgical treatment is required in 5–10% of
cases of chronic external or internal haemorrhoids.[24,25,108] Elective surgical treatment of internal haemorrhoids may be indicated when patients have grade 3 or 4 haemorrhoids, symptomatic
haemorrhoids associated with other benign anorectal conditions requiring surgery (e.g. fistula, fissure or stenosis) or continued symptoms despite
medical or minimally invasive measures.[108]
MPFF reduces the risk of bleeding following
elective haemorrhoidectomy according to data
from one trial (section 4.3.4). The proportion of
patients with secondary postoperative bleeding
after open pedicular haemorrhoidectomy was less
in patients treated with MPFF 500mg (2 tablets
three times daily for 3 days then 1 tablet three times
daily for 4 days) than in patients in the control
group (0.9 vs 6.1%). The duration of treatment
with MPFF (7 days) may not have been long
Drugs 2003; 63 (1)
Micronised Purified Flavonoid Fraction: A Review
enough; bleeding occurred day 6–15 after surgery
in the control group (mean 11.3 days) and day 14
in the patient with bleeding in the MPFF group.
7.4 Conclusions
In conclusion, MPFF is a well established and
well tolerated treatment option for patients with
CVI, venous ulcers, or acute or chronic internal
haemorrhoids. MPFF is indicated as a first-line
treatment of oedema and the symptoms of CVI in
patients in any stage of the disease. In more advanced disease stages, MPFF may be used in conjunction with sclerotherapy, surgery and/or compression therapy, or as an alternative treatment
when surgery is not indicated or is unfeasible. The
healing of venous ulcers ≤10cm in diameter is accelerated by the addition of MPFF to standard venous ulcer management (compression therapy and
local treatment); the addition of MPFF appears to
be cost effective. MPFF may reduce the duration
and/or intensity of symptoms of grade 1 or 2 acute
internal haemorrhoids. Although the duration of
treatment with MPFF for the prevention of relapse
of acute internal haemorrhoids remains to be clarified, the frequency of acute symptoms and the severity of the signs and symptoms of chronic haemorrhoids may be reduced with long-term MPFF
treatment.
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Correspondence: Katherine A. Lyseng-Williamson, Adis International Limited, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, Auckland 10, New Zealand.
E-mail: [email protected]
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